Function of saitohin, a novel protein that confers susceptibility to dementia Saitohin (STH), a gene encoding an open reading frame of 128 amino acids, is located in the intron between exons 9 and 10 of the human tau gene. It bears no obvious homology to any known protein or motif and its expression pattern is very similar to that of tau in human tissues. STH is present and expressed exclusively in the primates most closely related to humans (chimpanzee, bonobo and gorilla). A single polymorphism of human STH has been identified that changes glutamine residue 7 to arginine (Q7R). This polymorphism is associated with the two tau gene haplotypes: the Q allele with H1, the R allele with H2. The Q allele is the most common haplotype in humans but the STH of all nonhuman primates is homozygous for the R allele, which makes the Q allele a human-specific marker. In addition to evolution a study, the STH R allele seems to be associated with Alzheimer's disease (AD) specifically resulting from the ApoE4 susceptibility factor. Conversely, the Q allele has been shown to be over-represented in several neurodegenerative diseases: progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) and Parkinson's disease (PD). These results suggest that identifying a function of STH could implicate several proteins and/or pathways involved in neurodegeneration. Using STH in a yeast two-hybrid screening, we identified Peroxiredoxin 6 (Prdx6) as one of its ligands. We confirmed this interaction by additional assays and discovered that the two STH alleles show differential interactions with Prdx6. Prdx6 is a unique peroxiredoxin that has the antioxidant function common to all the family members and an additional phospholipase activity. Besides its role in normal cells, Prdx6 is elevated in Pick's disease (PiD), a disorder related to PSP and FTD. Additionally, Prdx6 dephosphorylates tau and this activity is enhanced by one of the STH alleles. These findings led us to form the hypothesis that STH influences tau function through its allele-specific interaction with Prdx6. In this exploratory grant, we will test this theory. We will investigate which of the two Prdx6 functions is influenced by STH, and how the STH/Prdx6 interaction modulates tau phosphorylation (including identification of the regions of each molecule required for interaction and of the tau residue(s) affected by this interaction). We will also examine where STH localizes, how the two STH alleles influence cells which do not express them (P19 mouse teratocarcinoma) and how STH suppression influences cells which express them (SY5Y human neuroblastoma) - specifically: process length and extension rate; localization of Prdx6 and selected cytoskeletal markers; endogenous tau splicing, phosphorylation and microtubule affinity. Function of saitohin, a novel protein that confers susceptibility to dementia. These studies will clarify the function(s) of STH and its connection to normal brain function and neurodegeneration. It may also help explain the unique susceptibility of our species to the woes of senility. [unreadable] [unreadable] [unreadable]